Antimicrobial peptides acting on cellular membranes have been found in most of the species in the world. Recently, researchers have paid attention to antimicrobial peptides to overcome the problems of conventional antibiotics, i.e., the increase of antibiotic resistant bacteria. Especially, after the first finding of bombinins from Bombina variegate in 1969, the skin of anurans (frogs and toads) has proven to be a rich source of antimicrobial peptides, which have a broad-spectrum of antimicrobial activities. After the discovery of an antimicrobial peptide from the African toenail frog, i.e., magainins in 1987, the antimicrobial peptides from frog skin has been a focus for potential therapeutic agents.
Since antimicrobial peptides kill bacteria by acting on the bacteria cell membrane and destroying the membrane selectively, the mechanism of an antimicrobial peptide is quite different from that of the existing antibiotics and is valuable as an alternative method for overcoming resistance problems. Furthermore, since the antimicrobial peptides have a broad spectrum of antimicrobial activity against gram-positive microbes, gram-negative microbes, fungi, viri and tumor cells, a natural substance isolated from a natural resource is expected to be a good antibiotic showing no side effects. Additionally, since it shows amphipathic properties, i.e., soluble in both water and lipid, it is expected to have great advantages in respect to drug absorption, drug transportation, etc. However, in spite of the favorable advantages of antimicrobial peptides, there remain several problems, such as, structural stability, bulky M. W., etc; in developing an antimicrobial peptide as a drug. The big problems of antimicrobial antibiotics are stability and molecular weight, as follows. First, in respect to stability, the antimicrobial peptides are easily decomposed due to great quantities of protein lyases existing in vivo. These problems can be solved by introducing unnatural derived amino acids, such as, D-amino acid, beta-amino acid, modifying their chemical structures and similar techniques. However, another problem, i.e., the bulky size of antimicrobial peptides having molecular weights greater than 3,000 still remains to be solved to correct the problems in respect to drug absorption, drug transportation, etc.
Anticancer agents can be classified into three categories, i.e., a bio-engineered drug, such as, anticancer drugs using gene, enzyme, vaccine etc; a synthesized drug and a natural product-derived drug. However, there remain several problems, for example, most bio-engineered drugs have not been developed in a clinical anticancer agent; and many chemotherapeutic agents have diverse pharmacological mechanism in accordance with the type of cancer (Gillman et al., The pharmacological Basis of therapeutics, Maxwell Macmillan., 18, p 1202, 1986) and toxic side effects (Chung et al., J. Wonkwang Medical ScL, 3, pp 13-34, 1987). Specifically, anticancer agents show toxic effects not only on cancer cells but also on normal cells. Also, there is resistance to anticancer agents caused by several factors, i.e., the mutation during growth, proliferation and metastasis of cancer cells. Since most anticancer agents have molecular weights less than 1,000 Dalton, the administered anticancer agents were absorbed in cancer cells, as well as, normal tissue resulting in damage to normal cells, especially, actively cell-dividing normal cells, for example, dysfunction of bone marrow, gastrointestinal disorders, alopecia, etc. Due to the low molecular weight, it is easily excreted through urine and therefore a great amount of an agent is required to obtain a desirable medical effect.
Therefore, the present inventors have endeavored to overcome the previously reported problems of antibiotic peptides and anticancer agents, and experimented to find effective and novel peptides showing more a potent efficacy than previously reported. Finally, they have found that novel synthesized analogues based on Gaegurin 5, the smallest length among six kinds of antimicrobial peptides previously designated as Gaegurin isolated from Korean frog, i.e., Gaegurins 1 to 6, showed potent antimicrobial, anticancer and non-hemolytic activity.